Cystic fibrosis arises from mutations in a single gene, which encodes a protein that forms a channel through which chloride ions pass in and out of cells. Errors in this protein, called the cystic fibrosis transmembrane conductance regulator (CFTR), can lead to the accumulation of thick, sticky mucus. The buildup of mucus has the most deadly effects in the lungs, where it can cause potentially fatal breathing problems or respiratory infections.

Although cystic fibrosis is a human disorder, many animals also express CFTR. When the human protein proved difficult to work with in the lab, researchers instead turned to the more-cooperative zebrafish version. Among other things, they used it to map the location of disease-causing mutations--findings that can now be applied to studying how the faulty human protein can spark disease.

Now, the scientists have mapped the three-dimensional structure CFTR. And it looks fishy. In research described in Cell, the researchers report that the human structure is almost identical to one they have determined previously for the zebrafish version of the protein.

"With these detailed new reconstructions, we can begin to understand how this protein functions normally, and how errors within it cause cystic fibrosis," says the senior author. "We now know that the conclusions we drew from our previous work in zebrafish also apply to us."

With new clues from the human structure, the researchers went on to explore the mechanism by which the channel becomes activated and the events that lead it to open and close.

The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, authors propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR.

From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR’s channel function
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http://newswire.rockefeller.edu/2017/03/23/new-study-resolves-the-structure-of-the-human-protein-that-causes-cystic-fibrosis/

http://www.cell.com/cell/abstract/S0092-8674(17)30239-8?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867417302398%3Fshowall%3Dtrue